The evolution of click chemistry: from classical reactions to next-generation platforms.
- 1Institute of Nanoscale and Biobased Materials, Faculty of Materials Science and Technology, TU Bergakademie Freiberg Gustav-Zeuner-Str. 3 09599 Freiberg Germany [email protected].
- 2Institute for Experimental Molecular Imaging, RWTH Aachen University Hospital Forckenbeckstraße 55 52074 Aachen Germany.
- 3Ardena Oss Kloosterstraat 9 5349 AB Oss The Netherlands.
Abstract
Click chemistry has transformed modern synthetic chemistry by providing efficient, selective, and modular strategies for constructing complex molecular structures. Since its introduction, the field has expanded from classical synthetic reactions to bioorthogonal and next-generation click platforms, broadening its applications across organic synthesis, polymer science, materials engineering, chemical biology, medicinal chemistry, and biomedicine. This review summarizes the evolution of click chemistry across three major generations. The first generation includes classical reactions such as copper-catalyzed azide-alkyne cycloaddition (CuAAC), thiol-ene, thiol-yne, thiol-ene Michael addition (TEMA), Diels-Alder (DA) cycloadditions, and nucleophilic ring-opening reactions. The second generation focuses on bioorthogonal transformations, including Strain-Promoted Alkyne-Azide Cycloaddition (SPAAC), Strain-Promoted Alkyne-Nitrone Cycloaddition (SPANC), and inverse electron-demand Diels-Alder (IEDDA) reactions, which enable selective chemical modification in living systems. The third generation encompasses emerging platforms such as sulfur(vi) fluoride exchange (SuFEx) and phosphorus(v) fluoride exchange (PFEx), which provide enhanced structural tunability, external control, and broader application potential. For each reaction class, the review discusses fundamental mechanisms, key advantages, limitations, and representative applications, highlighting how click chemistry has evolved from efficient bond formation toward increasingly precise chemical control in biological and materials environments.
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BibTeX
@article{dadfar2026evolution,
title = {{The evolution of click chemistry: from classical reactions to next-generation platforms.}},
author = {Seyed Mohammad Mahdi Dadfar and Seyed Mohammadali Dadfar},
journal = {RSC advances},
year = {2026},
month = oct,
doi = {10.1039/d6ra08128b},
url = {https://europepmc.org/article/MED/42846518},
note = {CC BY},
}
RIS
TY - JOUR
TI - The evolution of click chemistry: from classical reactions to next-generation platforms.
AU - Seyed Mohammad Mahdi Dadfar
AU - Seyed Mohammadali Dadfar
PY - 2026
DA - 2026/10/07
JO - RSC advances
DO - 10.1039/d6ra08128b
UR - https://europepmc.org/article/MED/42846518
AB - Click chemistry has transformed modern synthetic chemistry by providing efficient, selective, and modular strategies for constructing complex molecular structures. Since its introduction, the field has expanded from classical synthetic reactions to bioorthogonal and next-generation click platforms, broadening its applications across organic synthesis, polymer science, materials engineering, chemical biology, medicinal chemistry, and biomedicine. This review summarizes the evolution of click chemistry across three major generations. The first generation includes classical reactions such as copper-catalyzed azide-alkyne cycloaddition (CuAAC), thiol-ene, thiol-yne, thiol-ene Michael addition (TEMA), Diels-Alder (DA) cycloadditions, and nucleophilic ring-opening reactions. The second generation focuses on bioorthogonal transformations, including Strain-Promoted Alkyne-Azide Cycloaddition (SPAAC), Strain-Promoted Alkyne-Nitrone Cycloaddition (SPANC), and inverse electron-demand Diels-Alder (IEDDA) reactions, which enable selective chemical modification in living systems. The third generation encompasses emerging platforms such as sulfur(vi) fluoride exchange (SuFEx) and phosphorus(v) fluoride exchange (PFEx), which provide enhanced structural tunability, external control, and broader application potential. For each reaction class, the review discusses fundamental mechanisms, key advantages, limitations, and representative applications, highlighting how click chemistry has evolved from efficient bond formation toward increasingly precise chemical control in biological and materials environments.
SN - 2046-2069
ER -